The risk of osteoporotic fracture can be viewed as a function of loading conditions and the ability of human bone to withstand the load. Bone geometry is an important predictor of skeletal fragility;skeletal loads are dominated by muscle action. Bone geometry and muscle mass are both heritable and share genetic determinants. The proposed work will take advantage of available cohorts with large numbers of adult men and women with bone and muscle measures available, as well as extant genome-wide polymorphisms. Following the population- and family-based genome-wide association analyses in Framingham Osteoporosis Study (FOS), our results will be replicated in men and women from other US Caucasian cohorts, namely Cardiovascular Health Study (CHS), Pennsylvania Amish families, and siblings from Indiana, as well as the Rotterdam Study from the Netherlands and AGES-Reykjavik from Iceland. The OVERALL GOAL of the proposed project is to discern genetic factors contributing to two phenotypes that play an important role in the determination of bone strength. Our specific aims are: AIM 1. To perform genome-wide association analyses for cross-sectional bone geometry and muscle mass in the lower extremity in the Framingham Study, and then to identify chromosomal regions/ candidate genes shared by bone geometry and muscle mass. AIM 2. To replicate association findings in other Caucasian samples with the same (or similar) phenotypes, to select candidate regions for the follow-up. AIM 3. To explore gene-by-gene and gene-by-environment interaction on the bone/muscle interface. Identifying significant genetic variants underlying both bones and muscles, measured with state-of-art technology and replicated in other large cohorts, will provide valuable insight into important potential targets for risk stratification and may translate into new approaches to the prevention and personalized therapy for osteoporotic fractures. PUBLIC HEALTH RELEVANCE: The identification of these genes that influence osteoporosis and sarcopenia could lead to (i) earlier identification of people at risk, to implement preventive strategies, (ii) the development of more effective medications and more individualized therapy, and (iii) better knowledge how the genes and selected environment work together to regulate both muscle strength and the risk for osteoporosis. The above will improve substantially quality of life and decrease health care costs for millions of middle-aged and elderly Americans.